Stone, Will J. R.Campo, Joseph J.Ouédraogo, André LinMeerstein-Kessel, LisetteMorlais, IsabelleDa, DariCohuet, AnnaNsango, SandrineSutherland, Colin J.van de Vegte-Bolmer, MargaSiebelink-Stoter, Riannevan Gemert, Geert-JanGraumans, WouterLanke, KjerstinShandling, Adam D.Pablo, Jozelyn V.Teng, Andy A.Jones, Sophiede Jong, Roos M.Fabra-García, AmandaBradley, JohnRoeffen, WillLasonder, EdwinGremo, GiulianaSchwarzer, EvelinJanse, Chris J.Singh, Susheel K.Theisen, MichaelFelgner, PhilMarti, MatthiasDrakeley, ChrisSauerwein, RobertBousema, TeunJore, Matthijs M.2018-03-202018Stone, W. J. R., J. J. Campo, A. L. Ouédraogo, L. Meerstein-Kessel, I. Morlais, D. Da, A. Cohuet, et al. 2018. “Unravelling the immune signature of Plasmodium falciparum transmission-reducing immunity.” Nature Communications 9 (1): 558. doi:10.1038/s41467-017-02646-2. http://dx.doi.org/10.1038/s41467-017-02646-2.http://nrs.harvard.edu/urn-3:HUL.InstRepos:35015044Infection with Plasmodium can elicit antibodies that inhibit parasite survival in the mosquito, when they are ingested in an infectious blood meal. Here, we determine the transmission-reducing activity (TRA) of naturally acquired antibodies from 648 malaria-exposed individuals using lab-based mosquito-feeding assays. Transmission inhibition is significantly associated with antibody responses to Pfs48/45, Pfs230, and to 43 novel gametocyte proteins assessed by protein microarray. In field-based mosquito-feeding assays the likelihood and rate of mosquito infection are significantly lower for individuals reactive to Pfs48/45, Pfs230 or to combinations of the novel TRA-associated proteins. We also show that naturally acquired purified antibodies against key transmission-blocking epitopes of Pfs48/45 and Pfs230 are mechanistically involved in TRA, whereas sera depleted of these antibodies retain high-level, complement-independent TRA. Our analysis demonstrates that host antibody responses to gametocyte proteins are associated with reduced malaria transmission efficiency from humans to mosquitoes.en-USJournal Article2018-03-2010.1038/s41467-017-02646-2